A salt of pemetrexed are pemetrexed (represented by the structure of formula I) lithium salts, sodium salts and potassium salts and the like, in which sodium salts, i.e., pemetrexed sodium is a sodium salt of pemetrexed, including a monosodium salt, a disodium salt and a trisodium salt, etc. The most common sodium salt is a disodium salt, i.e., pemetrexed disodium, which has a structure of formula II and a chemical name of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-glutamic acid disodium salt. Various methods for preparing pemetrexed and pemetrexed disodium were disclosed in patents EP432677, EP589720, WO0011004, EP549886 and CN1778797.

Pemetrexed disodium is a multi-targeted antifolate that strongly inhibits various folate-dependent enzymes, including thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT). Pemetrexed disodium has been proved effective on a wide variety of solid tumors in clinical trials. At present, pemetrexed disodium is commercial available in USA, the European Union and China etc., which is used for treating malignant pleural stromal tumor as a first-line drug, and local advanced and metastatic non-small cell lung cancer as a second-line drug. In the treatment of malignant pleural stromal tumor, pemetrexed disodium is a unique chemotherapeutic agent in the market currently. In the second-line treatment of non-small cell lung cancer, pemetrexed disodium has a comparative efficacy and reduced toxicities compared with the standard drug Docetaxel, thus, it is hopeful for pemetrexed disodium to become a new standard drug of the second-line treatment for non-small cell lung cancer. In addition, the clinical studies of pemetrexed disodium in the treatment of breast, bowel, pancreatic, head and neck, gastric and bladder cancers are ongoing.
Purification is one of important procedures in the processes for preparing drug materials, and it directly affects the quality of the final products and the cost. At present, all disclosed methods for purifying pemetrexed disodium are crystallization methods using a mixture of an organic solvent and water. WO9916742 and WO0114379 disclose a crystallization method using a mixture of 3A ethanol and water heated to 60-70° C.; Organic Process Research & Development, 1999, 3:184-188, CN1778797 and CN1778802 disclose a crystallization method using a mixture of ethanol and water heated to 45-50° C.; CN1406238 and WO0114379 disclose a crystallization method using a mixture of acetone and water heated to 45-50° C.; furthermore, WO0114379 also discloses a crystallization method using a mixture of isopropanol and water heated to 60-65° C.
In the above methods for purifying pemetrexed disodium, it is generally required to purify pemetrexed prior to the formation of salts at the same time. At present, all disclosed purification methods of pemetrexed are also crystallization methods using a mixture of solvents. J. Med. Chem., 1992, 35:4450-4454 discloses a recrystallization method using a mixture of methanol and acetone; EP432677 discloses a recrystallization method using a mixture of methanol and dichloromethane; CN1406238 discloses a crystallization method using a mixture of 3A ethanol and water heated to 65° C.; Organic Process Research & Development, 1999, 3:184-188 discloses a crystallization method using a mixture of ethanol and water heated to 70-75° C.
Thus, all of the current purification methods of pemetrexed disodium and pemetrexed relate to a crystallization process comprising heating a mixture of solvents. Since pemetrexed disodium and pemetrexed are liable to be oxidized, their oxidation rates will be accelerated under a heating condition, thereby the quality and recovery of the products is reduced. In addition, a mixture of organic solvents is used in the current purification method, thereby the difficulty of recovery or disposal of the solvents and the costs increases greatly.
The present invention made an improvement on the problems existing in the purification methods of pemetrexed disodium in the prior art, such as reduced quality of products under a heating condition and difficulties of recovery and disposal of mixed solvents. It is surprising to find that a salting-out method can be used for purifying pemetrexed disodium effectively. Furthermore, this method can be carried out under a non-heating condition while not using an organic solvent. Accordingly, the present invention provides a method for improving the purification of pemetrexed disodium under a non-heating condition wherein an organic solvent can be avoid using.